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Mol Cell Biol, July 1998, p. 4131-4140, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Tyrosine 1101 of Tie2 Is the Major Site of
Association of p85 and Is Required for Activation of
Phosphatidylinositol 3-Kinase and Akt
Christopher D.
Kontos,1
Thomas P.
Stauffer,2
Wen-Pin
Yang,3
John D.
York,4
Liwen
Huang,1
Michael A.
Blanar,3
Tobias
Meyer,2 4 and
Kevin G.
Peters1 4 *
Departments of
Medicine,1
Cell
Biology,2 and
Pharmacology and Cancer
Biology,4 Duke University Medical Center,
Durham, North Carolina 27710, and
Department of Cardiovascular
Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research
Institute, Princeton, New Jersey 085433
Received 4 December 1997/Returned for modification 28 January
1998/Accepted 28 April 1998
Tie2 is an endothelium-specific receptor tyrosine kinase that is
required for both normal embryonic vascular development and tumor
angiogenesis and is thought to play a role in vascular maintenance. However, the signaling pathways responsible for the function of Tie2
remain unknown. In this report, we demonstrate that the p85 subunit of
phosphatidylinositol 3-kinase (PI3-kinase) associates with Tie2 and
that this association confers functional lipid kinase activity.
Mutation of tyrosine 1101 of Tie2 abrogated p85 association both in
vitro and in vivo in yeast. Tie2 was found to activate PI3-kinase in
vivo as demonstrated by direct measurement of increases in cellular
phosphatidylinositol 3-phosphate and phosphatidylinositol 3,4-bisphosphate, by plasma membrane translocation of a green fluorescent protein-Akt pleckstrin homology domain fusion protein, and
by downstream activation of the Akt kinase. Activation of PI3-kinase
was abrogated in these assays by mutation of Y1101 to phenylalanine,
consistent with a requirement for this residue for p85 association with
Tie2. These results suggest that activation of PI3-kinase and Akt may
in part account for Tie2's role in both embryonic vascular development
and pathologic angiogenesis, and they are consistent with a role for
Tie2 in endothelial cell survival.
*
Corresponding author. Mailing address: Box 3623, Duke
University Medical Center, Durham, NC 27710. Phone: (919) 684-2119. Fax: (919) 684-8591. E-mail: kgp{at}hodgkin.mc.duke.edu.

Present address: Myriad Genetics, Inc., Salt Lake City, UT
84105.
Mol Cell Biol, July 1998, p. 4131-4140, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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[Abstract]
[Full Text]
-
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[Abstract]
[Full Text]
-
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[Abstract]
[Full Text]
-
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(1999). Phosphatidylinositol 3-Kinase-dependent Membrane Association of the Bruton's Tyrosine Kinase Pleckstrin Homology Domain Visualized in Single Living Cells. J. Biol. Chem.
274: 10983-10989
[Abstract]
[Full Text]
-
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(2000). Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc. Natl. Acad. Sci. USA
97: 1749-1753
[Abstract]
[Full Text]